The present invention relates to new peptide mimetics for the treatment of bone disorders, methods for their production, and drugs containing these compounds.
In healthy individuals. the formation and degradation processes in the bones are virtually at equilibrium, i.e., the activity of the osteoblasts and osteociasts is balanced. However, if this equilibrium is disturbed in favor of the osteoclasts and/or to the disadvantage of the osteoblasts, a reduction in bone mass and a negative change in bone structure and function will be the result.
Up to now, bone resorption inhibitors such as estrogens, calcitonin and bisphosphonates are primarily used in the treatment of bone metabolic disorders. However, the use of these substances is limited and in addition, does not show the desired effect in all of the cases. Compounds having a stimulating effect on bone formation and contributing to increase an already diminished bone mass are therefore of particular importance in the treatment of bone disorders.
It is known that PTHrP(107-111) and the peptide derivatives thereof have a positive influence on the inhibition of bone resorption (WO 9210511; WO 9424153). However, Valin et al. in J. Cell Physiol. 170(2), 209-15 (1997), describe an anti-proliferative effect of PTHrP(107-111) on UMR106 cells. Whitfield et al. in J. Cell Physiol. 166(1), 1-11 (1996), demonstrate a stimulating effect on the PKC and a modulation of keratinocyte proliferation by PTHrP(107-111), whereas Kali et al. in Endocrinology 136(3), 842-8 (1995), describe a stimulation of the osteoclasts by PTHrP(107-111).
Surprisingly, it has now been found that the peptide mimetics of the present invention have a stimulating effect on bone formation and thus, are suitable for the general treatment of bone disorders. In particular, they can be used quite well in those cases where bone formation is disturbed, i.e., they are particularly suited for the treatment of osteopenic diseases of the skeletal system, such as osteoporosis, brittle bone disease among others, as well as for the local promotion of bone regeneration and osteoinduction as, e.g., in orthopedic and orthodontic indications, in fracture curing, osteosyntheses, pseudarthroses and for bone implants to become incorporated.
Due to these properties, they are also used in the prophylaxis of osteoporosis.
Moreover, due to their influence on the bone metabolism, drugs containing the peptide mimetics of the present invention as active substances constitute a basis for the local and systemic treatment of rheumatoid arthritis, osteoarthritis and degenerative arthrosis.
The present invention is directed to compounds of general formula (I) 
wherein
R1, R2, R3 and X may be the same or different, and wherein
R1, R2 represent hydrogen, an amino, peptidyl, alkyl or aryl residue;
R3 represents hydroxy, lower alkoxy, or an xe2x80x94NR31R32 residue, where R31, R32 and represent idependently hydrogen an amino acid, peptidyl, alkyl or aryl residue;
X represents an amino acid or a peptide.
R4 represents hydrogen, hydroxy, amino or C1-C4-alkyl;
m represents a number between 0 and 5;
R5 represents an optionally substituted saturated or unsaturated mono- or bicyclic moiety which may contain one or more heteroatoms, a C1-C11 alkyl group which may have substitutions or intermittent heteroatoms;
their tautomers, optical isomers, pharmaceutically acceptable salts and prodrugs.
X is preferably a xcfx89-Amino acid or the dipeptide serinylalaryl;
R4 represents preferably methyl or hydroxy;
R1 and R2 are independently of each other preferably hydrogen;
R3 is preferably hydroxy or amino;
m is preferably 1 to 3, more preferably 1;
The residue (CHR4)mR5 represents especially preferred a residue attached to Cxcex1 of a proteinogenic or non-proteinogenic amino acid.
Alkaline salts, earth alkaline salts like Ca or Mg salts, ammonium salts, acetates or hydrochlorides are mainly used as pharmacologically acceptable salts which are produced in the usual manner e.g. by tritrating the compounds with inorganic or organic bases or inorganic acids such as e.g. sodium hydroxide, potassium hydroxide, aqueous ammonia, C1-C4-alkyl-amines such as e.g. triethylamine or hydrochloric acid. The salts are usually purified by reprecipitation from water/acetone.
Prodrugs of the compounds of the invention are such which are converted in vivo to the pharmacological active compound. The most common prodrugs are carboxylic acid esters, like ethylesters.
Peptidyl represents are peptide residue. Peptide is understood to be a residue consisting of 2 to 10 proteinogenic or non-proteinogenic identical or different amino acids. Peptides having 2-5 amino acids are preferred; particularly preferred are those having 2 amino acids.
Amino acid residue normally means the residue of a proteinogenic or non-proteinogenic amino acid. Non-proteinogenic amino acids are understood to be xcex1-, xcex2-, xcex3-, and xcfx89-aminocarboxylic acids which may optionally have substitutions or intermittent heteroatoms.
Preferred xcfx89-amino acids are xe2x80x94HNxe2x80x94(CH2)nxe2x80x94COxe2x80x94with n=1-10; the xe2x80x94(CH2)n-group may be branched or unbranched.
Examples of such amino acids are the L- and D-amino acids, like 2-amino-3-hydroxy-4-methylpentanoic acid, 2-amino-3-hydroxy-4-methylpentanoic acid, 2-amino-3-methoxybutanoic acid, 2,3-diaminopropionic acid, 2-amino-2-methyl-3-hydroxypropanoic acid, 2-amino-2-methylbutanedioic acid, 2-amino-3-hydroxy-3-methylbutanoic acid, 2-amino-3-hydroxy-3-methylbutanoic acid, 2,3-diaminopropionic acid, 2-amino-2-methyl-3-hydroxypropanoic acid, 2-amino-2-methylbutanedioic acid, 2-amino-2-methylbutanoic acid, 2-amino-2-methyl-4-pentenoic acid, 2-amino-3-methoxypropanoic acid, 1-amino-1-cyclohexanecarboxylic acid, 1-amino-1-cyclopentanecarboxylic acid, 1-aminocyclobutanecarboxylic acid, 1-aminocyclopropanecarboxylic acid, 2-(2-furyl)glycine, 2-amino-3-fluorobutyric acid, 2-aminoisobutyric acid, 3-chloroalanine, 3-fluoronorleucine, 3-fluorovailne, 3-fluoroalanine, 3-methoxyvaline, alpha-cyanoalanine, alpha-methylleucine, beta-chloroalanine, beta-cyanoalanine, beta-hydroxyleucine, beta-hydroxyaspartic acid, 3-hydroxyaspartic acid, 2-aminobutyric acid, allylglycine, gamma-methylleucine, homoserine, norleucine, norvaline, tert-leucine, 2,3-diaminopropionic acid, 2,3-diaminosuccinic acid, 2-amino-4-pentenoic acid, 2-aminobutyric acid. 2-aminoheptanoic acid, 2-cyclopropyl-2-methylglycine, 4-thiaisoleucine, allothreonine, alpha-methylaspartic acid, alpha-methylserine, beta-hydroxynorvaline, beta-methylaspartic acid, homocysteine, homoserine, norleucine, norvaline, O-methylserine, penicillamine, propargaylglycine, beta-hydroxyaspartic acid vinylglycine, beta-hydroxyaspartic acid, H-4,5-dehydro-LEU-OH, H-alpha-MeVAL-OH, H-propargayl-GLY-OH, H-allo-ILE-OH, H-PRA-OH, H-trans-4,5-dehydroLYS-OH, 3-hydroxyaspartic acid, 6-hydroxynorleucine, allo-isoleucine, allyl glycine, alpha-amino-N-butyric acid, gamma-methylleucine, homoserine, norvaline, penicillamine, tert-leucine, vinylglycine, meso-alpha beta-diaminosuccinic acid, O-carbamoyl-serine, S-methylcysteine, 2-amino-2-methylbutanedioic acid, 2-fluoro-beta-alanine, beta-alanine, beta-aminobutyric acid, 2,3-diaminosuccinic acid, beta-aminoisobutyric acid, isoserine,
Preferred amino acids are alanine, serine, tryptophan, tyrosine, phenylalanine, threonine, histidine, citrulline, homocysteine, homoserine, hydroxyproline, hydroxylysine, ornithine, sarcosine, tranexamic acid, Cha (cyclohexylalanine), aminobutyric acid, aminovaleric acid, and aminopropionic acid.
Lower alkoxy denote methoxy, ethoxy, propoxy, ispropoxy or butoxy, preferably methoxy.
Alkyl normally means linear or branched alkyl residues having from one to six carbon atoms.
Aryl normally means a carbocyclic moiety having from 6 to 14 C atoms or a 5- or 6-membered heterocyclic moiety having 1, 2 or 3 heteroatoms selected from O, N, S, which moiety may optionally have one or multiple substitutions, with unsubstituted or optionally substituted phenyl or naphthyl residues being preferred.
Monocyclic moiety is understood to be a saturated or unsaturated ring system having 3-8, preferably 5-7 carbon atoms, which may optionally have one or multiple intermittent heteroatoms such as nitrogen, oxygen or sulfur, particularly a cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, thiamorpholinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, or 1,2,4-triazolyl residue. In particular, lower alkyl, alkoxy and halogen are possible as substituents.
Preferably, the bicyclic moiety referred to under R5 is a residue such as a naphthyl, tetrahydronaphthyl, decalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, indazolyl, oxindolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl or purinyl residue, but particularly an indolyl, naphthyl, benzimidazolyl, quinolinyl, tetrahydroquinolinyl, benzothiophenyl, and benzofuranyl residue.
The term xe2x80x9cseveralxe2x80x9d means in connection with heteroatoms in monocycles or bicycles preferred one, two or three more preferred one or two, the most preferred heteroatom is nitrogen.
The term xe2x80x9cseveralxe2x80x9d means in connection with substituents or substitution preferred one to five, more preferred one, two or three most preferred one or two.
Substitutions of monocycles or bicycles in R5 are halozen. nitro, hydroxy, alkoxy, amino, alkylamino, dialkylamino, halogenmethyl, dihalogenmethyl, trihalogenmethyl, phosphono, alkylphosphono, dialkylphosphono, SO2NH2, SO2NH(alkyl), SO2N(alkyl)2, S2(alkyl), acetyl, formyl, nitril, COOH, COOalkyl, xe2x80x94OC(O)alkyl, xe2x80x94NHC(O)Oalkyl, OC(O)Oxe2x80x94aryl, xe2x80x94NHC(S)NH2, xe2x80x94NHC(S)NHalkyl, xe2x80x94NHC(O)xe2x80x94aryl.
Preferred substituents are methyl, ethyl, propyl, isopropyl, halogenyl, especially chloro, amino, acetyl, alkylamino, dialkylamino, alkoxy, hydroxyalkyl, and C0-C4 alkylcarbonic acids.
The preparation of the compounds of general formula (I) is achieved according to per se known methods. Advantageously, the preparation is effected using the precursors (II), (III) and (IV), respectively, 
wherein Y represents a carboxyl group, according to the procedure outlined in Schemes 1, 2 and 3.
Compounds of general formula (IV) are new and useful for orthogonal syntheses of compounds which comprise the backbone structure of (IV). The preferred residue for R9 is Fmoc. 
Steps a) through d) in Scheme 1 represent the following reactions:
a) NaBH3CN/MeOH/RT;
b) PhCOCl/py/DMAP/RT;
c) DBU/toluene/RT/16 hrs;
d) DIBAL-H/THF/xe2x88x9278xc2x0 C.;
wherein R6 represents a protecting group, e.g., the benzoyl group, an alkyloxycarbonyl group or the benzyloxycarbonyl group, and R7 represents hydrogen or lower alkyl such as methyl, ethyl, propyl, butyl or tert-butyl, R8 represents an alkyl or aryl residue such as a methyl, ethyl, trifluoromethyl, phenyl, tosyl or the 4-nitrophenyl residue, but preferably the methyl or tosyl residue, and L normally represents a sulfonic acid residue such as the methane- or trifluoromethanesulfonic acid or the p-toluenesulfinic acid residue, or halogen such as chlorine, bromine, iodine, or acetate.
MHal represents a metal halide such as NaCl, NaBr, KI, MgCl2 or MgBr2.
Compounds of formula (5) have been described (J.O.C. 48, 1129-31 (1983)). The conversion of an alcohol of formula (5) to a sulfonic or acetic ester of formula (6) is effected according to standard procedures. The transformation of an alcohol of formula (5) into a halide of formula (6) using N-chloro-, N-bromo- or N-iodosuccinimide (NCS, NBS, NIS) in the presence of triphenylphosphine (Ph3P) is performed in analogy to the corresponding literature procedures (e.g., Tetrahedron Asym. 4, 1619-24 (1993)). The decarboxylation of malonic esters using metal halides in DMSO at elevated temperatures is well-known (T.L. 957 (1973)). Compounds of formula (9) have been described (JACS 114, 7324-25 (1992)). The epoxide opening of a compound of formula (10) to yield an allyl alcohol of formula (11) is carried out in analogy to the literature (Tetrahedron 24, 5827-30 (1968)). The conversion of a compound of formula (13) to a compound of general formula (II) by means of a Claisen rearrangement is performed in analogy to the literature (Tetrahedron 52, 941-54 (1996)). 
Steps a) through f) in Scheme 2 represent the following reactions:
a) Ac2O/pyridine/DMAP
b) 4 N HCl/16 hrs; (14)/EtN(i-Pr)2 
c) (16), R7=Et/HMDS/n-BuLi/xe2x88x9278xc2x0 C.
d) 1 N HCl/THF/RT/30 minutes
e) Boc2O/EtN(i-Pr)2/acetonitrile/16 hrs
f) LiOH/THF-MeOH-H2O
wherein R6 and R7 have the above-mentioned meanings. 
Steps a) through e) in scheme represent the following reactions:
a) HDMS/n-BuLi/xe2x88x9278xc2x0 C.
b) CH3COOH/THF/RT/30 minutes
c) R9Cl/EtN(i-Pr)2/THF/16 hrs
d) 4 N HCl/dioxane
e) EtN(i-Pr)2/acetonitrile
wherein R6 and R7 have the above-mentioned meanings and R9 represents another protecting group such as Fmoc or Troc.
The compounds of formula (I) may be administered in liquid or solid form or as aerosols on the oral, enteral, parenteral, topical, nasal, pulmonary or rectal routes in all the common non-toxic, pharmaceutically accepted carriers. adjuvants and additives. The compounds of formula (I) may also be applied locally on/in bones (optionally with surgical operation). The term xe2x80x9cparenteralxe2x80x9d includes subcutaneous, intravenous and intramuscular supply or infusions. Oral administration forms may be, e.g., tablets, capsules, coated tablets, syrups, solutions, suspensions, emulsions, elixirs, etc., which may contain one or more additives from the following groups, e.g., flavoring substances, sweeteners, colorants. and preservatives. Oral administration forms contain the active component together with non-toxic, pharmaceutically accepted carriers suitable for the production of tablets, capsules, coated tablets, etc. such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; starch, mannitol, methylcellulose, talc, highly dispersed silicic acids, higher molecular weight fatty acids (such as stearic acid), peanut oil, olive oil, paraffin, Miglyol, gelatin, agar-agar, magnesium stearate, beeswax, cetyl alcohol, lecithin, glycerol, animal and vegetable fat, solid high molecular weight polymers (such as polyethylene glycols). Tablets, capsules, coated tablets, etc. may be provided with an appropriate coating such as glyceryl monostearate or glyceryl distearate, so as to prevent undesirable side effects in the stomach, or to result in prolonged activity due to delayed absorption in the gastrointestinal tract. Sterile injectable aqueous or oily solutions or suspensions are preferably used as injection media, which contain common additives such as stabilizers and solubilizers. Such additives may be, e.g., water, isotonic saline solution, 1,3-butanediol, fatty acids (such as oleic acid) mono- and diglycerides, or Miglyol. For rectal administration, all the suitable non-irritating additives may be used which are solid at normal temperatures and liquid at rectal temperature, such as cocoa butter and polyethylene glycol. For aerosol administration, the pharmaceutically common carrier media are used. For external application, creams, tinctures, gels, solutions or suspensions with pharmaceutically common additives are used. The dosage may depend on various factors such as the mode of application, species, age and/or individual condition. The doses administered daily or at intervals are around 1-1000 mg/person, preferably around 10-250 mg/person and may be ingested at one go or distributed over several times.
The compounds of formula (I) may be applied locally on/in bones (optionally with surgical operation). The application directly on/in bones (optionally with surgical operation) may be effected either in solution or suspension, conveniently by infusion or injection, locally or carrier-bound. For example, carrier-bound compounds of formula (I) may be applied as gels, pastes, solids or as coating on implants.
As carriers, biocompatible and preferably, biodegradable materials are used. Preferably, the materials themselves will additionally induce wound healing or osteogenesis.
For local application it is preferred to embed the compounds of formula (I) in polymeric gels or films, thereby immobilizing them, and to apply these preparations directly on the point of the bone to be treated. These polymeric base gels or films consist of, e.g., glycerol, methylcellulose, hyaluronic acid, polyethylene oxides and/or polyoxamers. Collagen, gelatin and alginates are also suitable and are described in WO 93/00050 and WO 93/20859, for example. Other polymers are polylactic acid (PLA) and copolymers of lactic acid and glycolic acid (PLPG) (Hollinger et al., J. Biomed. Mater. Res. 17 71-82 (1983)), and the xe2x80x9cDemineralized Bone Matrixxe2x80x9d (DBM) bone derivative (Guterman et al., Kollagen Rel. Res. 8, 419-4319 (1988)). Polymers such as those used for adsorbing TGFB, for example, are also suitable and are described in EP-A 0,616,814 and EP-A 0,567,391. as well as the synthetic bone matrices according to WO 91/18558.
Materials commonly used when implanting bone substitutes or other therapeutically active substances are also suitable as carriers for the compounds of formula (I). Such carriers are also based on, e.g., calcium sulfate, tricalcium phosphate, hydroxyapatite and its biodegradable derivatives, and polyanhydrides. Apart from these biodegradable carriers, those carriers are also suitable which are not biodegradable but are biocompatible. For example, these carriers are sintered hydroxyapatite, bioglass, aluminates or other ceramic materials (e.g., calcium aluminate phosphate). Preferably, these materials are used in combination with said biodegradable materials, such as, in particular, polylactic acid, hydroxyapatite, collagen, or tricalcium phosphate. Other non-degradable polymers have been described in the U.S. Pat. No. 4,164,560, for example.
Particularly preferred is the use of carriers which continuously release the compounds of formula (I) at the site of action. Especially suited for this purpose are, e.g., the xe2x80x9cslow release pelletsxe2x80x9d by Innovative Research of America, Toledo, Ohio, USA. Particularly preferred is the use of pellets releasing the compounds of formula (I) over several days, preferably up to 100 days, at a daily dose of 1-10 mg/kg per day.
Apart from the compounds mentioned in the examples, and the compounds which may be derived by combining all the meanings of the substituents mentioned in the claims, the following derivatives, as well as their pharmacologically acceptable salts, particularly the hydrochlorides and trifluoroacetates are preferred in the meaning of the present invention.
Index of abbreviations used:
Aba=aminobutyric acid
Ac=acetyl
Ada=(1-amidino-2,5-dihydro-1H-pyrrol-3-yl)alanine
Ala=aanine
Ava=aminovaleric acid
Bn=benzyl
Boc=tert-butyloxycarbonyl
Bu=butyl
Cbz=benzyloxycarbonyl
Cha=cyclohexylalanine
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene
DIBAL-H=diisobutylaluminum hydride
DMAP=4-dimethylaminopyridine
DMF=dimethylformamide
Et=ethyl
Fmoc=9-fluorenylmethoxycarbonyl
Gly=glycine
HMDS=hexamethyldisilazane
i-Pr=isopropyl
Me=methyl
NMM=N-methylmorpholine
Ph=phenyl
Phe=phenylalanine
Pro=proline
py=pyridine
RT=room temperature
Ser=serine
t-Bu=tert-butyl
TBTU=2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetratfluoroborate
TCP=trityl chloride-polystyrene
THF=tetrahydrofuran
Thr=threonine
Troc=2,2,2-trichloroethoxycarbonyl
Trp=tryptophan
Tyr=tyrosine
tB=retention time
Val=valine
ln addition the one-letter code for amino acids is used.
Within the sense of the present invention the following peptide mimetics are preferred in addition to the compounds mentioned in the examples and compounds that can be derived by combining all meanings of substituents mentioned in the claims in the preferred compounds.
Preferred compounds:
1) 2-{5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylam+ino]-pentanoylamino}-3-(indol-2-yl)-propionic acid
2) 2-{5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-(7-methyl-indol-2-yl)-propionic acid
3) 2-{5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-benzo[b]thiophen-2-yl-propionic acid
4) 2-{5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-(6-methyl-indol-2-yl)-propionic acid
5) 2-{5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-(6-hydroxy-indol-2-yl)-propionic acid
6) 2-{5-[2-Amino3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-(3-methyl-indol-2-yl)-propionic acid
7) 2-{5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5 -dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-(3-methyl-benzofuran-2-yl)-propionic acid
8) 2-{5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-(3,4dimethyl-benzofuran-2-yl)-propionic acid
9) 2-{5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-(3,5-dimethyl-benzoruran-2-yl)-propionic acid
10) 2-{5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-y1)-propionylamino]-pentanoylamino}-3-(3,6-dimethyl-benzofuran-2-yl)-propionic acid
11) 2-{5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5 -dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-(5-ethyl-3-methyl-benzofuran-2-yl)-propionic acid
12) 2-{5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-hydroxy-3-(3-methyl-benzofuran-2-yl)-propionic acid
13) 2-{5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-(3,7-dimethyl-benzofuran-2-yl)-propionic acid
14) 2-{5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-(7-ethyl-3-methyl-benzofuran-2-yl)-propionic acid
15) 2-{5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}3-(3,6-(3,6-dimethyl-benzofuran-2-yl)3-hydroxy-propionic acid
16) 2-{5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionamino]-pentanoylamino}-3-(3,5-dimethyl-benzofuran-2-yl)-3-hydroxy-propionic acid
17) 2-{5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}3-(3,4-dimethyl-benzofuran-2-yl)-3-hydroxy-propionic acid
18) 2-{5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-(3,7-dimethyl-benzofuran-2-yl)-3-hydroxy-propionic acid
19) 2-{5-[2-(2-Amino-3-hydroxy-butyrylamino)-3(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-(7-chloro-3-methyl-benzofuran-2-yl)-3-hydro propionic acid
20) 2-{5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-(5-ethyl-3-methyl-benzofuran-2-yl)-3-hydroxy-propionic acid
21) 2-{5-[2(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-(7-ethyl-3-methyl-benzofuran-2-yl)-3-hydroxy-propionic acid
22) 2-{5-[2-Amino-3-(1-carbamimimdoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-furan-2-yl-propionic acid
23) 2-{5-[2-(2-Amino-3-hydroxy-butyrylamino)-3(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-furan-2-yl-3-hydroxy-propionic acid
24) {5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-thiophen-2-yl-acetic acid
25) 2-{5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-thiophen-2-yl-propionic acid
26) 2-{5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-(pyrrol-2-yl)-propionic acid
27) 2-{5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-(5-methyl-thiophen-2-yl)-propionic acid
28) 2-{5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-hydroxy-3-(5-methyl-thiophen-2-yl)-propionic acid
29) 2-{5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-(5-ethyl-thiophen-2-yl)-propionic acid
30) 2-{5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-(5-propyl-thiophen-2-yl)-propionic acid
31) 2-{5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-(5-hydroxymethyl-furan-2-yl)-propionic acid
32) 5-(2-{5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]pentanoylamino}-2-carboxy-ethyl)-2-methyl-furan-3-carboxylic acid
33) 5-(2-{5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-2-carboxy-ethyl)-2-ethyl-furan-3-carboxylic acid
34) 5-(2-{5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-2-carboxy-ethyl)-2-methyl-pyrrol-3-carboxylic acid ethyl ester
35) 5-(2-{5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-2-carboxy-ethyl)-2-propyl-furan-3-carboxylic acid
36) 3-(5-Acetylimino-4,5-dihydro-thiophen-2-yl)-2-{5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}3-hydroxy-propionic acid
37) 5-(2-{5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-2-carboxy-ethyl)-2-isobutyl-furan-3-carboxylic acid
38) 2-{5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-cyclopent-1-enyl-propionic acid
39) 2-{5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-hydroxy-3-thiophen-2-yl-propionic acid
40) {5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-(3-methyl-benzo[b]thiophen-7-yl)-acetic acid
41) {5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-phenyl-acetic acid
42) 2-{5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-(3,4-dihydroxy-phenyl)-3-hydroxy-propionic acid
43) {5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-(4-hydroxy-phenyl)-acetic acid
44) 2-{5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino-3-phenyl-butyric acid
45) 2-{5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-(3,4-bis-benzyloxy-phenyl)-3-hydroxy-propionic acid
46) 2-{5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-hydroxy-succinic acid
47) 2-({5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-carboxy-methyl)-benzoic acid
48) 5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-(3-oxo-2,3-dihydro-isoxazol-5-yl)-acetic acid
49) {5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-cyclohexyl-acetic acid
50) {5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-cyclohexa-1,4-dienyl-acetic acid
51) {5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-cyclohexa-1,5-dienyl-acetic acid
52) 2-{5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-hydroxy-3-pyridin-3-yl-propionic acid
53) 2-{5-[2-(2-Amino-3-hydroxy-butyrylamino)-3(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-hydroxy-3-pyridin-4-yl-propionic acid
54) 4({5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino)-carboxy-methyl)-2-hydroxy-benzoic acid
55) 4-({5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-carboxy-methyl)-benzoic acid
56) 2-{5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-3-phenylsulfanyl-butyric acid
57) {5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-(tetrazol-5-yl)-acetic acid
58) {5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-(indol-3-yl)-acetic acid
59) {5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-(3,4-dihydroxy-phenyl)-acetic acid
60) {5-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-pentanoylamino}-(3,5-dihydroxy-phenyl)-acetic acid
61) 2-{4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(indol-2-yl)-propionic acid
62) 2-{4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(7-methyl-indol-2-yl)-propionic acid
63) 2-{4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-benzo[b]thiophen-2-yl-propionic acid
64) 2-{4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(6-methyl-indol-2-yl)-propionic acid
65) 2-{4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(6-hydroxy-indol-2-yl)-propionic acid
66) 2-{4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(3-methyl-indol-2-yl)-propionic acid
67) 2-{4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(3-methyl-benzofuran-2-yl)-propionic acid
68) 2-{4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(3,4-dimethyl-benzofuran-2-yl)-propionic acid
69) 2-{4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(3,5-dimethyl-benzofuran-2-yl)-propionic acid
70) 2-{4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(3,6-dimethyl-benzofuran-2-yl)-propionic acid
71) 2-{4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(5-ethyl-3-methyl-benzofuran-2-yl)-propionic acid
72) 2-{4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-hydroxy-3-(3-methyl-benzofuran-2-yl)-propionic acid
73) 2-{4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino)-3-(3,7-dimethyl-benzofuran-2-yl)-propionic acid
74) 2-{4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(7-ethyl-3-methyl-benzofuran-2-yl)-propionic acid
75) 2-{4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(3,6-dimethyl-benzofuran-2-yl)-3-hydroxy-propionic acid
76) 2-{4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(3,5-dimethyl-benzofuran-2-yl)-3-hydroxy-propionic acid
77) 2-{4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(3,4-dimethyl-benzofuran-2-yl)-3-hydroxy-propionic acid
78) 2-{4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(3,7-dimethyl-benzofuran-2-yl)-3-hydroxy-propionic acid
79) 2-{4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(7-chloro-3-methyl-benzofuran-2-yl)-3-hydroxy-propionic acid
80) 2-{4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(5-ethyl-3-methyl-benzofuran-2-yl)-3-hydroxy-propionic acid
81) 2-{4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(7-ethyl-3-methyl-benzofuran-2-yl)-3-hydroxy-propionic acid
82) 2-{4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-furan-2-yl-propionic acid
83) 2-{4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-furan-2-yl-3-hydroxy-propionic acid
84) {4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-thiophen-2-yl-acetic acid
85) 2-{4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-thiophen-2-yl-propionic acid
86) 2-{4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(pyrrol-2-yl)-propionic acid
87) 2-{4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(5-methyl-thiophen-2-yl)-propionic acid
88) 2-{4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-hydroxy-3-(5-methyl-thiophen-2-yl)-propionic acid
89) 2-{4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(5-ethyl-thiophen-2-yl)-propionic acid
90) 2-{4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(5-propyl-thiophen-2-yl)-propionic acid
91) 2-{4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(5-hydroxymethyl-furan-2-yl)-propionic acid
92) 5-(2-{4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-2-carboxy-ethyl)-2-methyl-furan-3-carboxylic acid
93) 5-(2-{4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-2-carboxy-ethyl)-2-ethyl-furan-3-carboxylic acid
94) 5-(2-{4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-2-carboxy-ethyl)-2-methyl-pyrrole-3-carboxylic acid ethyl ester
95) 5-(2-{4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-2-carboxy-ethyl)-2-propyl-furan-3-carboxylic acid
96) 3-(5-Acetylimino-4,5-dihydro-thiophen-2-yl)-2-{4-[2-(2-amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-hydroxy-propionic acid
97) 5-(2-{4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-2-carboxy-ethyl)-2-isobutyl-furan-3-carboxylic acid
98) 2-{4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-cyclopent-1-enyl-propionic acid
99) 2-{4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-hydroxy-3-thiophen-2-yl-propionic acid
100) {4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-(3-methyl-benzo[b]thiophen-7-yl)-acetic acid
101) {4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-phenyl-acetic acid
102) 2-{4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-(3,4-dihydroxy-phenyl)-3-hydroxy-propionic acid
103) {4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-(4-hydroxy-phenyl)-acetic acid
104) 2-{4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-phenyl-butyric acid
105) 2-{4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol3-yl)-propionylamino]-butyrylamino}-3-(3,4-bis-benzyloxy-phenyl)-3-hydroxy-propionic acid
106) 2-{4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-hydroxy-succinic acid
107) 2-({4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-carboxy-methyl)-benzoic acid
108) 5-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-(3-oxo-2,3-dihydro-isoxazol-5-yl)-acetic acid
109) {4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-cyclohexyl-acetic acid
110) {4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-cyclohexa-1,4-dienyl-acetic acid
111) {4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-cyclohexa-1,5-dienyl-acetic acid
112) 2-{4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-hydroxy-3-pyridin-3-yl-propionic acid
113) 2-{4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-hydroxy-3-pyridin4-yl-propionic acid
114) 4-({4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-carboxy-methyl)-2-hydroxy-benzoic acid
115) 4-({4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-carboxy-methyl)-benzoic acid
116) 2-{4-[2-(2-Amino-3-hydroxy-butyrylamino)-3(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-3-phenylsulfanyl-butyric acid
117) {4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-(tetrazol-5-yl)-acetic acid
118) {4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-(indol-3-yl)-acetic acid
119) {4-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-(3,4-dihydroxy-phenyl)-acetic acid
120) {4-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-butyrylamino}-(3,5-dihydroxy-phenyl)-acetic acid
121) 2-{3-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-3-(indol-2-yl)-propionic acid
122) 2-{6-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-hexanoylamino}-3-(7-methyl-indol-2-yl)-propionic acid
123) 2-(2-{2-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-3-hydroxy-propionylamino}-propionylamino)-3-benzo[b]thiophen-2-yl-propionic acid
124) 2-{3-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-3-(6-methyl-indol-2-yl)-propionic acid
125) 2-{6-[2-(2-Amino-3-hydroxy-butyrylamino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-hexanoylamino}-3-(6-hydroxy-indol-2-yl)-propionic acid
126) 2-(2-{2-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-3-hydroxy-propionylamino}-propionylamino)-3-(3-methyl-indol-2-yl)-propionic acid
127) 2-{3-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-3-(3-methyl-benzofuran-2-yl)-propionic acid
128) 2-(2-{2-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-3-hydroxy-propionylamino}-propionylamino)-3-(3,4-dimethyl-benzofuran-2-yl)-propionic acid
129) 2-{6-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-hexanoylamino}-3-(3,5-dimethyl-benzofuran-2-yl)-propionic acid
130) 2-(2-{2-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-3-hydroxy-propionylamino}-propionylamino)-3-(5-ethyl-3-methyl-benzofuran-2-yl)-propionic acid
131) 2-{3-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-3-hydroxy-3-(3-methyl-benzofuran-2-yl)-propionic acid
132) 2-(2-{2-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-3hydroxy-propionylamino}-propionylamino)3-(3,7-dimethyl-benzofuran-2-yl)-propionic acid
133) 2-{6-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-hexanoylamino}-3-(7-ethyl-3-methyl-benzofuran-2-yl)-propionic acid
134) 2-(2-{2-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-3-hydroxy-propionylamino}-propionylamino)-3-(3,6-dimethyl-benzofuran-2-yl)-3-hydroxy-propionic acid
135) 2-{3-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-3-(3,5-dimethyl-benzofuran-2-yl)-3-hydroxy-propionic acid
136) 2-(2-{2-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-3-hydroxy-propionylamino}-propionylamino)-3-(3,4-dimethyl-benzofuran-2-yl)-3-hydroxy-propionic acid
137) 2-{6-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-hexanoylamino}-3-(3,7-dimethyl-benzofuran-2-yl)-3-hydroxy-propionic acid
138) 2-(2-{2-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-3-hydroxy-propionylamino}-propionylamino)-3-(7-chloro-3-methyl-benzofuran-2-yl)-3-hydroxy-propionic acid
139) 2-{3-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-3-(5-ethyl-3-methyl-benzofuran-2-yl)-3-hydroxy-propionic acid
140) 2-{6-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-hexanoylamino}-3-(7-ethyl-3-methyl-benzofuran-2-yl)-3-hydroxy-propionic acid
141) 2-{6-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-hexanoylamino}-3-furan-2-yl-propionic acid
142) 2-{3-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-3-furan-2-yl-3-hydroxy-propionic acid
143) {3-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-thiophen-2-yl-acetic acid
144) 2-(2-{2-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-3-hydroxy-propionylamino}-propionylamino)-3-thiophen-2-yl-propionic acid
145) 2-{6-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-hexanoylamino}-3-(pyrrol-2-yl)-propionic acid
146) 2-{3-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-3-(5-methyl-thiophen-2-yl)-propionic acid
147) 2-(2-{2-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-3-hydroxy-propionylamino}-propionylamino)-3-(5-ethyl-thiophen-2-yl)-propionic acid
148) 2-{3-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-3-(5-propyl-thiophen-2-yl)-propionic acid
149) 2-(2-{2-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-3-hydroxy-propionylamino}-propionylamino)-3-(5-hydroxymethyl-furan-2-yl)-propionic acid
150) 5-(2-{6-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-hexanoylamino}-2-carboxy-ethyl)-2-methyl-furan-3-carboxylic acid
151) 5-(2-(2-{2-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-3-hydroxy-propionylamino}-propionylamino)-2-carboxy-ethyl)-2-ethyl-furan-3-carboxylic acid
152) 5-(2-{3-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-2-carboxy-ethyl)-2-methyl-pyrrole-3-carboxylic acid ethyl ester
153) 5-(2-{6-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-hexanoylamino}-2-carboxy-ethyl)-2-propyl-furan-3-carboxylic acid
154) 5-(2-{3-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-carboxy-ethyl)-2-isobutyl-furan-3-carboxylic acid
155) (2-{2-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-3-hydroxy-propionylamino}-propionylamino)-3-cyclopent-1-enyl-propionic acid
156) 2-{3-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-3-hydroxy-3-thiophen-2-yl-propionic acid
157) 2-{6-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-hexanoylamino}-3-(3,4-dihydroxy-phenyl)-3-hydroxy-propionic acid
158) 2-{3-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-3-phenyl-butyric acid
159) 2-(2-{2-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-3-hydroxy-propionylamino}-propionylamino)-3-(3,4-bis-benzyloxy-phenyl)-3-hydroxy-propionic acid
160) 2-{6-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-hexanoylamino}-3-hydroxy-succinic acid
161) {3-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-cyclohexa-1,4-dienyl-acetic acid
162) 2-{3-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-3-hydroxy-3-pyridin-3-yl-propionic acid
163) 4-({6-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-hexanoylamino}-carboxy-methyl)-2-hydroxy-benzoic acid
164) 2-{3-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-3-phenylsulfanyl-butyric acid
165) {6-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-hexanoylamino}-(indol-3-yl)-acetic acid
166) {3-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-(3,5-dihydroxy-phenyl)-acetic acid
167) (2-{2-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-propionylamino)-3-(6-hydroxy-indol-2-yl)-propionic acid
168) (2-{2-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-propionylamino)-3-(3,6-dimethyl-benzofuran-2-yl)-propionic acid
169) 2-(2-{2-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-propionylamino)-3-(3,4-dimethyl-benzofuran-2-yl)-3-hydroxy-propionic acid
170) 2-(2-{2-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-propionylamino )-3-(7-ethyl-3-methyl-benzofuran-2-yl)-3-hydroxy-propionic acid
171) 2-(2-{2-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-propionylamino)-3-thiophen-2-yl-propionic acid
172) 2-(2-{2-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-propionylamino)-3-(5-methyl-thiophen-2-yl)-propionic acid
173) 2-(2-{2-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-propionylamino)-3-(5-hydroxymethyl-furan-2-yl)-propionic acid
174) 3-(5-Acetylimino-4,5-dihydro-thiophen-2-yl)-(2-{2-[-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-propionylamino)-3-hydroxy-propionic acid
175) (2-{2-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-propionylamino)-phenyl-acetic acid
176) (2-{2-[2-Amino-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-propionylamino)-3-(3,4-dihydroxy-phenyl)-3-hydroxy-propionic acid
177) 2-(2-{2-[2-(2-Amino-3-hydroxy-butylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-propionylamino)-3-(3,4-bis-benzyloxy-phenyl)-3-hydroxy-propionic acid
178) 2-((2-{2-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-propionylamino)-carboxy-methyl)-benzoic acid
179) 2-(2-{2-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-propionylamino)-3-hydroxy-3-pyridin-4-yl-propionic acid
180) (2-{2-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-propionylamino)-(tetrazol-5-yl)-acetic acid
181) (2-{2-[2-(2-Amino-3-hydroxy-butyrylamino)-3-(1-carbamimidoyl-2,5-dihydro-pyrrol-3-yl)-propionylamino]-propionylamino}-propionylamino)-(3,4-dihydroxy-phenyl)-acetic acid
The following examples exemplify variants for the synthesis of the compounds of the invention. The structure of the compounds was obtained by 1Hxe2x80x94, 13C-NMR-s spectroscopy and optionally by mass-spectroscopy. The purity of the substances was obtained by C, H, N analyses and by chromatography.